This proposal determines if immunization of mice with OspA or OspB will prevent tick-transmitted Lyme borreliosis. Using a C3H mouse model of Lyme borreliosis, we have shown that immunization with recombinant outer surface protein A or B (OspA, OspB) from Borrelia burgdoferi (Bb) protected mice from infection following intradermal challenge with syringe-inoculum of Bb. We also showed that ticks can be cleared of Bb (strain N40) through feeding on mice immunized with OspA-N40. The efficacy of induced immunity, however, against a realistic vector- mediated challenge remains unexplored. This proposal will determine if the OspA and OspB immunogens protect mice against Bb delivered by nymphal lxodes dammini ticks. Ticks infected with cloned laboratory strains of Bb and ticks collected in the wild will be used in the challenge experiments. We will evaluate how homologous recombination between OspA and OspB, Osp mutations and Osp heterogeneity influence protective immunity in realistic in vivo tick transmission studies. This work will increase our understanding of the mechanisms by which Bb may evade protective immunity and the ability to immunize against natural transmission of the Lyme disease agent.